Protein Helps Build Muscle Mass: Possible Treatment For Muscle Wasting Disorders

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Protein Helps Build Muscle Mass: Possible Treatment For Muscle

Wasting Disorders

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2008/12/081215111131.htm

Cowling et al. report how to build muscle mass with FHL1. The protein

partners with and activates the transcription factor, NFATc1.

Encouraging this partnership might provide a possible treatment for

muscle wasting disorders. The article will appear in the December 15,

2008 issue of The Journal of Cell Biology (JCB).

Mutations in FHL1 are present in several myopathies, including

reducing-body myopathy (RBM), but until now, both the molecular

mechanisms causing the disease, and the regular function of FHL1 in

healthy tissue, remained unknown.

To address this, Cowling et al. overexpressed FHL1 in both transgenic

mice and cultured myoblasts. The mice developed skeletal muscle

hypertrophy, and showed increased strength and endurance.

Overexpression in myoblasts also increased cell fusion, resulting in

hypertrophic myotubes. These phenotypes are similar to those caused

by the calcineurin/NFAT pathway and, indeed, inhibiting calcineurin

blocked the effects of FHL1 overexpression in vitro. The authors

showed that FHL1 binds to and enhances the transcriptional activity

of NFATc1 in vitro and in vivo.

So what goes wrong when FHL1 is mutated? In RBM, mutant FHL1

accumulates in cytoplasmic aggregates called reducing bodies,

probably as a result of misfolding. When these mutants were expressed

in cultured myoblasts, they also aggregated, and did not induce

hypertrophy. Cowling and colleagues found that NFATc1 was sequestered

to the aggregates, and was therefore unable to activate its target

genes.